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Nearly 13 years after her last “Star Wars” movie, Natalie Portman makes her long-awaited return to the science-fiction genre. Judging by the results, she should do it more often.

Based on the novel from Jeff VanderMeer, “Annihilation” is Alex Garland’s follow-up to his sublime directorial debut “Ex Machina.” While both ponder human nature, Garland’s sophomore directorial effort ditches the small-scale techno-thriller conceit for something much bigger and better.

Portman plays Lena, a biologist whose husband (Oscar Isaac) has returned from a restricted biological disaster zone called the Shimmer, which is protected by a colorful, otherworldly barrier. After escaping the Shimmer, Lena’s husband returns with dramatic changes in his personality and poor health. To complicate things further, the Shimmer is expanding, morphing everything that falls within its grasp.

Fueled by a desire to save her husband, Lena joins a team led by psychologist Dr. Ventress (Jennifer Jason Leigh) to go on an expedition into the Shimmer to gain some insight into its origin. Lena’s mission takes her on a journey that shatters her very notion of reality as she discovers a bizarre fusion of biological material across the area.

With any story that descends into the strange — as “Annihilation” definitely does — the audience needs to be grounded properly. Garland’s sharp script and the ensemble effectively accomplish that by mixing hard science with likeable characters, making what could’ve been a slog of a first half still intriguing to watch.

Portman brings a humanity that offsets an intentionally cold, unsettling performance from Oscar Isaac. Through a series of flashbacks, they effectively invoke a real, recognizable relationship that forms a strong emotional core. This core is complimented by a similarly realistic bond between Lena and the fellow women of the expedition. These are focused, strong characters whose interactions are tense, brimming with character.

Jennifer Jason Leigh brings forth the understated, ice queen mannerisms that have made her such a pleasure to watch on screen, while Tessa Thompson’s introvert and Gina Rodriguez’s brash wildcard play great foils to one another. Yet, all these performances take a backseat to the journey Garland has in store.

The Shimmer is a beautifully realized locale. The depiction is not exactly like it is described in the novel, and so much of the film diverges from the source material that “loose adaptation” is a more apt term. However, the Shimmer’s lush visuals are at once stylized and tangible, creating a world that truly lingers by enhancing familiar geography with trippy, unsettling colors and bizarre creatures, such as a crocodile with shark teeth. The more time we spend in the Shimmer, the better the film gets.

“Annihilation” goes from good to great with an encounter between the crew and a hybrid bear creature in an abandoned building. The pure fear the team experiences, and the gruesome lengths Garland is willing to go to convey that, are constant, and from that moment onward, there’s an exciting unease as to what exactly is going to happen.

Then, in the third act, Lena has an encounter with the creature at the heart of the Shimmer that solidifies Garland’s film as a masterpiece.

Helped by a startlingly original score by Geoff Barrow and Ben Salisbury, the film’s climax is a staggering, monumental achievement in filmmaking. The conclusion of “Annihilation” is a psychedelic rollercoaster that lets loose a stream of surreal, thought-provoking images.

Yet, even with all the showmanship, what puts “Annihilation” above the rest is in the question it makes the viewer ask: What happens when our perception of life itself is challenged? It’s not entirely clear on a first viewing exactly how Garland’s film answers that question, but maybe it doesn’t really need to.